4,5-disubstituted-2,3-epoxycyclo-pentanones

ABSTRACT

4,5-DISUBSTITUTED-3-HYDROXYCYCLOPENTANONES (I) ARE PREPARED BY HYDROGENOLYZING THE CORRESPONDING 4,5-DISUBSTITUTED-2,3-EPOXYCYCLOPENTANONE (IV) WHICH IN TURN IS PROVIDED BY REACTING THE CORRESPONDING 4,5-DISUBSTITUTED2-CYCLOPENTEN-1-ONE (III) WITH ALKALINE HYDROGEN PEROXIDE. COMPOUNDS III ARE PREPARED BY CYCLIZING THE CORRESPONDING 2,3-DISUBSTITUTED LEVULINALDEHYDE (II) WITH A BASE. THE PRODUCTS OF THE PROCESS ARE BIOLOGICALLY ACTIVE, ESPECIALLY COMPOUND I SUBSTITUTED IN THE 4-POSITION WITH 3&#39;&#39;-HYDROXYOCTYL AND IN THE 5-POSITION WITH 6&#39;&#39;-CARBOXYHEXYL. THIS COMPOUND HAS PROSTAGLANDIN-LIKE ACTIVITY, ESPECIALLY BLOOD PRESSURE LOWERING AND BRONCHODILATOR ACTIVITY, AND IS A TOTALLY-SYNTHETIC DIHYDROPROSTAGLANDIN E1 (DIHYDRO PGE1). THE PROCESS OF THE INVENTION MAY ALSO BE USED TO OBTAIN COMPOUNDS WITH PROSTAGLANDIN-LIKE ACTIVITY FROM APPROPRIATELY SUBSTITUTED NATURALLY OCCURRING CYCLOPENTANONES, E.G. THOSE ISOLATED FROM THE CARIBBEAN GORGONIAN, PLEXAURA HOMOMALLA.

'Unit d States Patent Olfic 3,736,336 Patented May 29, 1973 3,736,3364,5-DlSUBSTITUTED-2,3-EPOXYCYCLO- PENTANONES Donald P. Strike, Rosemont,and Herchel Smith, Bryn Mawr, Pa., assignors to American Home ProductsCorporation, New York, N.Y.

No Drawing. Application Nov. 12, 1969, Ser. No. 876,116, wihch is acontinuation-in-part of application Ser. No. 765,020, Oct. 4, 1968,which in turn is a continuationin-part of application Ser. No. 702,185,Feb. 1, 1968, all now abandoned. Divided and this application Apr. 15,1971, Ser. No. 134,465

Int. Cl. C07d 1/20, 1/22 US. Cl. 260345.7 Claims ABSTRACT OF THEDISCLOSURE 4,5-disubstituted-3hydroxycyclopentan0nes (I) are prepared byhydrogenolyzing the corresponding4,5-disubstituted-Z,3-epoxycyclopentanone (IV) which in turn is providedby reacting the corresponding 4,5-disubstituted- 2-cyclopenten-1-one(III) with alkaline hydrogen peroxide. Compounds III are prepared bycyclizing the corresponding 2,3-disubstituted levulinaldehyde (II) witha base. The products of the process are biologically active, especiallyCompound I substituted in the 4-position with 3'-hydroxyoctyl and in the5-position with 6-carboxyhexyl. This compound has prostaglandin-likeactivity, especially blood pressure lowering and bronchodilatoractivity, and is a totally-synthetic dihydroprostaglandin E (dihydroPG'E The process of the invention may also be used to obtain compoundswith prostaglandin-like activity from appropriately substitutednaturally occurring cyclopentanones, e.g. those isolated from theCaribbean gorgonian, Plexaura homomalla.

This application is a division of US. patent application Ser. No.876,116, filed Nov. 12, 1969, now abandoned, which in turn is acontinuation-in-part of copending application Ser. No. 765,020, filedOct. 4, 1968, now abandoned, which is in turn a continuation-in-part ofcopending Ser. No. 702,185, filed Feb. 1, 1968, and now abandoned.

This invention relates to valuable organic compounds, to processes fortheir preparation, and to intermediates useful in said processes. Moreparticularly, it is concerned with4,5-disubstituted-3-hydroxycyclopentanones, which have valuablepharmacological properties; with the corresponding 2,3-epoxides, andother valuable intermediates therefor, and with the processes to preparesaid compounds from known starting materials.

BACKGROUND OF THE INVENTION The compounds contemplated to be provided bythe instant invention are 4,5-disubstituted-3-hydroxycyclopentanones ofFormula I:

wherein R and R are alkyl radicals or alkyl radicals mono-substitutedwith carboxy, carbo(lower)alkoxy,

tetrahydropyranyloxy, hydroxy or (lower)acyloxy, the alkyl radicalscontaining from about 1 to about 20 carbon atoms. Compounds of Formula Iare pharmacologically active. In this connection, special mention ismade of the isomer of the compound of Formula I wherein the hydrogen (H)atoms at the 4- and 5-positions are in the trans-stereochemicalrelationship and wherein R is 3'-hydroxyoctyl and R is 6'-carboxyhexyl.This compound, also known as dihydroprostaglandin E (dihydro PGEpossesses potent blood pressure lowering, bronchodilating and otherpharmacodynamic activities. Its ureide and thiosemicarbazone derivativesalso have bronchodilating activity.

The term prostaglandin-like activity is used by those skilled in the artparticularly to descibe hypotensive and smooth muscle stimulatingactivity demonstrated by substituted cyclopentane derivatives having thebasic prostaglandin-type structure. This activity was discovered by vonEuler, Arch. Exp. Pathol. PharmakoL, 175, 78 (1934), in lipid-solubleacids extracted in small amounts from the vesicular glands of sheep, andin the seminal fluid of monkeys, sheep and goats. The structure of oneof these acids with prostaglandin-like activity was elucidated by S.Bergstrom and J. Sjovall, Acta Chem. Scand., 14, 1693, 1701, 1706(1960). The compound, 7-[3a-hydroxy 2(3-hydroxy-1-octenyl)-5-oxocyclopentyl]-heptanoic acid, also called PGEwas obtained in pure crystalline form, and then in smaller amounts, onlyafter organization of a program for the collection of frozen glands ofsheep in several countries in the northern hemisphere. With this sourceof PGE as starting material, it was then found (S. Bergstrom and J.Sjovall, United Kingdom patent specification No. 1,040,545) that PGEcould be hydrogenated using known catalysts for hydrogenating ethenoidunsaturation, for example, platinum catalyst, to the correspondingsaturated acid, dihydro PGE and that this compound possessed valuableprostaglandin-like activity. Other workers sought means to providedihydro PGE, and similar compounds without the need to isolate PGE fromanimal tissue and secretions. Thus, P. F. Beal, G. S. Fonken and J. E.Pike, in US. 3,296,091, describe the bioconversion of arachidonic acidby incubation with sheep vesicular gland tissue into PGE and disclosethat the dihydro PGE can be prepared by hydrogenation, and that it hasprostaglandinlike activity. In a typical example, the homogenate from18.7 kg. of tissue was used to convert only 35.3 g. of arachidonic acidinto a mixture of four prostaglandins, only one of which was PGE Inaddition to the prostaglandin-like activity reported for dihydro PGE M.Lapidus, N. H. Grant, M. E. Rosenthale and H. E. Alburn, in US. patentapplication, Ser. No. 672,728, filed Oct. 4, 1967 describe and claim theureido derivative thereof and in US. patent application, Ser. No.672,697, filed Oct. 4, 1967, describe and claim the thiosemicarbazonederivative thereof, and disclose that both of these compounds are highlypotent bronchodilating agents. In the present state of the art, asexemplified by the references cited above, prostaglandins are obtainedonly in very small quantities by isolation from tissues by biosyntheses,or by total syntheses, see, for example, George Just and ChaimSimonovitch, Tetrahedron Letters, No. 22, 2093 (1967); and P. F. BealIII, J. C. Babcock, F. H. Lincoln, J. Am. Chem. Soc., 88, 3131 (1966);and E J.

Corey et al., ibid., 90, 3245, 3247 (1968). A clear need, therefore,exists for improved means to provide these active and useful compounds.The present invention provides such a means, being concerned with atotally synthetic process to make the 4,5-disubstituted-3-hydroxycyclopentanone ring system present in the basic prostaglandin-typestructure as hereinafter defined.

It is a primary object of the present invention, therefore, to provide4,S-disubstituted-3-hydroxycyclopentanones by total synthesis fromreadily accessible starting materials.

It is another object to provide4,5-disubstituted-3-hydroxycyclopentanones with prostaglandin-likeactivity in high yield from readily accessible starting materialsincluding those of natural origin.

Still another object of this invention is to provide valuableintermediates useful in a totally synthetic process to prepare 4,5disubstituted-3hydroxycyclopentanones, such as dihydro PGE DESCRIPTIONOF THE INVENTION These and other objects readily apparent to thoseskilled in the art are easily achieved by practice of the means of theinstant invention which is, in essence:

First. A process for the preparation of a4,5-disubstituted-3-hydroxycyclopentanone compound of the formula:

HR R 11 O MNOH wherein R and R are alkyl radicals or alkyl radicalsmono-substituted with carboxy, carbo(lower)alkoxy, tetrahydropyranyloxy,hydroxy, or (lower)acyloxy, the alkyl radicals containing from about 1to about 20 carbon atoms, which comprises reacting a 4,5-disubstituted-2,3-epoxycyclopentanone compound of the formula:

wherein R and R are as defined above, with hydrogen in the presence of acatalyst until hydrogenolysis and formation of said4,5-di-substituted-3-hydroxycyclopentanone is substantially complete.

Special mention is made of a number of valuable embodiments of thisinvention. These are:

Second. A process as first above defined wherein 4-(3'- hydroxyoctyl) 5(6'-carboxyhexy1)-3-hydroxycyclopentanone is prepared by reacting4-(3-hydroxyoctyl)-5- (6-carboxyhexyl) -2,3-epoxycyclopentanone withhydrogen in the presence of a palladized charcoal catalyst.

Third. A process as first above defined wherein 4-(3'-tetrahydropyranyloxyoctyl) 5 (6-carboxyhexyl)-3-hydroxycyclopentanone isprepared by reacting 4-(3-tetrahydropyranyloxyoctyl)5-(6'-carboxyhexyl)-2,3-epoxycyclopentanone with hydrogen in thepresence of a palladized charcoal catalyst.

Fourth. A process as third above defined including the step of reactingsaid 4-(3-tetrahydropyranyloxyoctyl)-5- (6'-carboxyhexyl) 3hydroxycyclopentanone with an acidic hydrolyzing agent until formationof 4-(3-hydroxyoctyl) 5 (6-carboxyhexyl)-3-hydroxycyclopentanone issubstantially complete. The second and fourth embodiments provide thevaluable compound, dihydro PGE and its stereoisomers.

Fifth. A process as first above defined wherein 4,5-dirnethyl-3-hydroxycyclopentanone is prepared by react ing4,5-dimethyl-2,3-epoxycyclopentanone with hydrogen in the presence of apalladized charcoal catalyst.

Sixth. A process as first above defined wherein is inchided the a 915 ara i g aid t i ubstimeq-zsepoxycyclopentanone compound by a processwhich comprises contacting a 4,S-disubstituted-Z-cyclopenten-l one ofthe formula:

wherein R and R are alkyl radicals or alkyl radicals mono-substitutedwith carboxy, carbo(lower)alkoxy, tetrahydropyranyloxy, hydroxy or(lower)acyloxy, the alkyl radicals containing from about 1 to about 20carbon atoms, with alkaline hydrogen peroxide until formation of said4,S-disubstituted-Z,3-epoxycyclopentanone is substantially complete.

Seventh. A process as sixth above defined wherein 4- (3 hydroxyoctyl) 5(6'-carboxyhexyl)-2,3-epoxycyclopentanone is prepared by contacting4-(3-hydroxyoctyl) -5- 6-carboxyhexyl) -2-cyclopenten-1-one withalkaline hydrogen peroxide.

Eight. A process as sixth above defined wherein 4-(3'-tetrahydropyranyloxyoctyl) 5 (6-carboxyhexyl)-2,3- epoxycyclopentanoneis prepared by contacting 4-(3'- tetrahydropyranyloxyoctyl) 5(6-carboxyhexyl)-2-cyclopenten-l-one with alkaline hydrogen peroxide.

Ninth. A process as sixth above defined wherein 4,5-dimethyl-2,3-epoxycyc1opentanone is prepared by contacting4,S-dimethyl-Z-cyclopenten-l-one with alkaline hydrogen peroxide.

Tenth. A process as sixth above defined wherein is included the step ofpreparing said 4,5-disubstituted-2- cyclopenten-l-one compound by aprocess which comprises contacting a 2,3-disubstituted-levulinaldehydeof the formula:

wherein R and R are alkyl radicals or alkyl radicals mono-substitutedwith carboxy, car-bo(lower)alkoxy, tetrahydropyranyloxy, hydroxy or(lower)acyloxy, the alkyl radicals containing from about 1 to about 20carbon atoms, with a base until cyclization to said4,5-disubstituted-Z-cyclopenten-l-one is substantially complete.

Eleventh. A process as tenth above defined including the steps ofseparating, recovering and using as the intermediate in the subsequentsteps, the said 4,5-disubstituted cyclopentene compound wherein thehydrogen atoms at the 4- and 5-positions are in the trans-stereochemicalrelationship, substantially free of the cis-isomer.

This embodiment provides, ultimately, pure trans-dihydro PGE which is anaturally-occurring prostaglandin metabolite.

Twelfth. A process as tenth above defined wherein 4- (3'-hydroxyoctyl) 5(6-carboxyhexyl)-2-cyclopentenl-one is prepared by contacting2-(3-tetrahydropyranyloxyoctyl) 3 (6'-carbomethoxyhexyl)levulinaldehydewith a base, followed by acidic hydrolysis of the tetrahydropyranyloxygroup.

Thirteenth. A process as tenth above defined wherein4-(3-tetrahydropyranyloxyoctyl) 5 (6-carboxyhexyl)-2-cyclopenten-1-oneis prepared by contacting 2-(3'- tetrahydropyranyloxyoctyl)-3-(6'carbomethoxyhexyl) levulinaldehyde or a2-(3-tetrahydropyranyloxyoctyl)-3- (6'-carboethoxyhexyl)levulinaldehydewith a base.

Fourteenth. A process as tenth above defined wherein4,S-dimethyl-Z-cyclopenten-l-one is prepared by contacting2,3-dimethyllevulinaldehyde with a base.

Fifteenth. A process as thirteenth above defined including the steps of(a) Complexing hexanal with a reagent prepared by treating acetylenewith ethylmagnesium bromide and decomposing the Grignard complex formedthereby to produce oct-1-yl-3-ol;

(b) Condensing the product of step (a) with dihydro- CHO pyran underacidic conditions to produce 2-(oct-l-yn-3- yloxy) tetrahydropyran;

(c) Complexing the product of step (b) with ethyl magnesium bromide,reacting the complex with ethyl orthoformate and decomposing theintermediate found thereby to produce4-(tetrahydropyran-Z-yloxy)-2-nonynal, diethyl acetal;

(d) Reacting the product of step (c) with water under acid conditions toproduce 4-hydroxy-2-nonynal;

(e) Condensing the product of step (d) with dihydropyran under acidconditions to produce 4-(tetrahydropyran-2-yloxy)-2-nonynal;

(f) Hydrogenating the product of step (e) with a noble metal catalyst toproduce 4-(tetrahydropyran-Z-yloxy) nonanal;

(g) Complexing the product of step (f) with a reagent prepared bytreating propyne with ethylmagnesium bro mide and decomposing theGrignard complex formed thereby to produce 7(tetrahydropyran-Z-yloxy)-2-dodecyn-4-ol;

(h) Reacting t-butylacetoacetate with sodium hydride and condensing theanion formed thereby with ethyl 7- bromoheptanoate to produce2-acetylnonadioic acid, l-tbutyl ester, 9-ethyl ester:

(i) Esterifying the product of step (g) with methanesulfonyl chlorideunder basic conditions to produce 7- (tetrahydropyran-Z-yloxy)-2-dodecyn4 o1, methanesulfonate;

(j) Reacting the product of step (h) with sodium hydride and condensingthe anion formed thereby With the product of step (i) to produce2-acety1-2-[1-(1-pro yny1)- 4-(tetrahydropyran-2-yloxy)nonyl]nonanedioicacid, l-tbutyl ester, 9-ethyl ester;

(k) Hydrolyzing the product of step (j) under acidic conditions toproduce 2-acetyl-2-[4-hydroxy-l-(l-propynyl)nonyl] nonanedioic acid,l-t-butyl ester, 9-ethyl ester.

(1) Acetylating the product of step (k) with acetic anhydride andpyridine to produce 2-acetyl-2-[4-h'ydroxy-l-(l-propynyl)nonyl]nonanedioic acid, l-t-butyl ester, 9- ethyl ester,acetate;

(m) Monohydrogenating the product of step (I) with hydrogen and apalladium on calcium carbonate catalyst to produce 2-acetyl-2-[4-hydroxy- 1- 1-propyenyl)nonyl] nonanedioic acid, l-t-butyl ester,9-ethyl ester, acetate;

(11) Decarboxylating the product of step (m) with ptoluenesulfonic acidor with calcium iodide to produce 8- acetyl 12hydroxy-9-(l-propenyl)-heptadecanoic acid, ethyl ester, acetate;

(0) Saponifying the product of step (11) with aqueous ethanolic sodiumhydroxide to produce 8-acetyl-l2-hydroxy-9- 1-propenyl)heptadecanoicacid;

(p) Esterifying the product of step (0) with ethereal diazomethane toproduce 8-acetyl-12-hydroxy-9-(l-propenyl)heptadecanoic acid, methylester;

(q) Condensing the product of step (p) with dihydropyran under acidicconditions to produce8-acety1-l2-(tetrahydropyranyl-2-oxy)-9-(l-propenyl)heptadecanoic acid,methyl ester; or

(s) Decarboxylating the product of step (j) with calcium iodide toproduce 8-acetyl-12-hydroxy-9-(l-propynyl)heptadecanoic acid, ethylester; and

(t) Monohydrogenating the product of step (s) with hydrogen and apalladized charcoal catalyst to produce 8- acetyl 12hydroxy-9-(1-propenyl)heptadecanoic acid, ethyl ester; and

(u) Condensing the product of step (t) with dihydropyran under acidicconditions to produce 8-acetyl-9-(lpropenyl)-12 (tetrahydropyran 2yloxy)heptadecanoic acid, ethyl ester; or

(v) Condensing the product of step (s) with dihydropyran under acidicconditions to produce 8-acetyl-9-(1- propynyl) 12(tetrahydropyran-Z-yloxy)heptadecanoic acid, ethyl ester; and

(W) Monohydrogenating the product of step (v) with hydrogen and apalladized charcoal catalyst to produce 8 acetyl 9 (lpropenyl)-12-(tetrahydropyran-Z-yloxy) heptadecanoic acid, ethyl ester;and

(r) Ozonizing the product of step (q), (u) or (W), then decomposing theozonide produced thereby with zinc dust in acetic acid to produce2-(3'-tetrahydropyrany1oxyoctyl) -3- 6-carbomethoxyhexyl)levulinaldehyde or 2- (3 tetrahydropyranyloxyoctyl) 3 (6carboethoxyhexyl) levulinaldehyde.

Sixteenth. A process for the preparation of a 4,5-disubstituted 3hydroxycyclopentanone compound of the formula:

(dihydroprostaglandin E1) including the steps of (aa) Esterifying4-(3'-hydroxy-1'-octenyl)-5-(6'-carboxy-2-hexenyl)-2-cyclopenten-1-oneisolated from the Caribbean gorgonia Plexaura homomalla withmethanesulfonyl chloride under basic conditions to produce 4-(3-methanesulfonyloxy l octenyl)-5-(6'-carboxy-2-hexenyl)-2-cyclopenten-l-one;

(bb) Inverting the configuration of the oxy-substituent at the 3positionin the compound of step (aa) by refluxing in acetone withtetraethylammonium formate to produce 4 (3 forrnyloxy 1'octenyl)-5-(6-carboxy-2- hexeny1)-2-cyclopentenl-one;

(cc) Forming the epoxide of the compound of step (bb) and saponifyingthe product by reacting with alkaline hydrogen peroxide to produce4-(3'-hydroxy-1- octenyl)-5-(6'-carboxy-2'-hexenyl) 2,3epoxycyclopentanone;

(dd) Hydrogenating the compound of step (cc) with hydrogen in thepresence of a palladized charcoal catalyst to produce4-(3'-hydroxyoctyl)-5-(6'-carboxyhexyl) 3- hydroxycyclopentanone.

Also contemplated by the instant invention are compounds of the formulawherein R and R are alkyl radicals or alkyl radicals mono-substitutedwith carboxy, carbo(lower)alkoxy, tetrahydropyranoxy, hydroxy orlower(acyloxy), the alkyl radicals containing from about 1 to about 20carbon atoms. These compounds are valuable intermediates in the processof this invention. Special mention is made of several importantcompounds within the above formula. These are:

4- 3 -hydroxyocty1)-5-(6'-carboxyhexyl(2,3-epoxycyclopentanone (R is6'-carboxyhexyl; R is 3 '-hydroxyoctyl) 4- (3-acetoxyoctyl) -5-6'-carboethoxyhexyl) -2,3-

epoxycyclopentanone (R is fi-carboethoxyhexyl; R is 3'-acetoxyoctyl).

4- (3 'tetrahydropyranyloxyoctyl) -5-6'-carbomethoxyhexyl)-2,3-epoxycyclopentanone (R is 6'-carbomethoxyhexyl; R is 3'-tetrahydropyranyloxyoctyl) 4- (3-tetrahydropyranyloxyoctyl) -5- (6'-carboxyhexyl)2,3-epoxycyclopentanone (R is 6-carboxyhexyl; R is3'-tetrahydropyranyloxyoctyl) In addition there are contemplated:

4-(3-tetrahydropyranyloxyoctyl)-5-(6'-carbornethoxyhexyl)-2-cyclopenten-l-one.

4- (3 -tetrahydropyranyloxyoctyl) (6-carboxyhexyl) 2-cyclopenten-1-one.These form a family of compounds of the formula HR B B:

wherein R is 6'-carbomethoxyhexyl and R is 3-tetrahydr0pyranyloxyoctyl;and

R is 6-carboxyhexyl and R is 3'-tetrahydropyranyloxyoctyl, respectively.

In addition there is contemplated a sub-genus of compounds of Formula Iwhich are those of Formula Ia:

0R1 mom (1;) wherein R is hydrogen or (lower) alkyl (of up to about 6carbon atoms) and R is tetrahydropyranyl or acyl of from about 1 toabout carbon atoms,

Valuable species of Formula Ia are4-(3'-acetoxyoctyl)-5-(6'-carboethoxyhexyl)3-hydroxycyclopentanone,wherein R is ethyl and R is acetyl; and

4-(3-tetrahydropyranyloxyoctyl)-5-(6-carboxyhexyl)-3-hydroxycyclopentanone, wherein R is hydrogen and R istetrahydropyranyl.

Furthermore, there are contemplated as valuable intermediates thefollowing substituted levulinaldehydes:

2- (3 '-hydroxyoctyl) -3- (6'-carboxyhexyl) levulinaldehyde.

2- (3 '-tetrahydropyranyloxyoctyl) -3- (6'-carboxyhexyl)levulinaldehyde.

2- (3 '-tetrahydropyranyloxyoctyl) -3-(6'-carbomethoxyhexyl)levulinaldehyde.

2- (3 '-tetrahydropyranyloxyoctyl) -3 (6'-carboethoxyhexyl)levulinaldehyde.

2- (3 '-acetoxyo ctyl -3- (6'-carboethoxyhexy1) levulinaldehyde. Theseform a family of compounds of the formula wherein R is 6-carboxyhexy1and R is 3-hydroxyoctyl;

R is 6-carboxyhexyl and R is 3'-tetrahydropyranyloxyoctyl;

R is 6'-carbomethoxyhexyl and R is 3-tetrahydropyranyloxyoctyl;

R is 6-carboethoxyhexyl and R is 3-tetrahydropyranyloxyoctyl; and

R is 6-carboethoxyhexy1 and R is 3'-acetoxyoctyl,

respectively.

In addition, there are contemplated as valuable intermediates thefollowing:

8-acetyl-l2- (tetr ahydropyran-Z-yloxy) -9- l-propenyl) heptadecanoicacid, methyl ester.

8-acetyl-12-hydroxy-9-( l-propenyDheptadecanoic acid,

methyl ester.

8-acetyl-l2-hydroxy-9-(1-propenyl)heptadecauoic acid.

8-acety1-12-hydroxy-'9-(1-propenyl)-heptadecanoic acid,

ethyl ester, acetate.

8-acetyl-12-hydroxy-9-( l-propynyl)heptadecanoic acid,

ethyl e wherein R is methyl, R is hydrogen; R is tetrahydropyranyloxyand W is a carbon-to-carbon double bond;

R is methyl, R is hydrogen, R is hydroxy and W is a carb on-to-carbondouble bond;

R and R are hydrogen, R is hydroxy and W is a carbonto-carbon doublebond;

IR is ethyl, R is hydrogen, R is acetoxy and W is a carbon-to-carbondouble bond;

R is ethyl, R is hydrogen, R is hydroxy and W is a carbon-to-carbontriple bond;

R is ethyl, R is hydrogen, R is hydroxy and W is a carbon-to-carbondouble bond;

R is ethyl, R is hydrogen, R is tetrahydropyranyloxy and W is acarbon-to-carbon triple bond;

R is ethyl, R is hydrogen, R is tetrahydropyranyloxy and W is acarbon-to-carbon double bond;

R is ethyl, R is carbo-t-butoxy, R is acetoxy and W is acarbon-to-carbon double bond;

R is ethyl, R is carbo-t-butoxy, R is acetoxy and W is acarbon-to-carbon triple bond;

R is ethyl, R is carbo-t-butoxy, R is hydroxy and W is acarbon-to-carbon triple bond; or

R is ethyl, R is carbo-t-butoxy, R is tetrahydropyranyloxy and W is acarbon-to-carbon triple bond.

Also contemplated as an intermediate is: Z-acetylnonadioic acid,l-t-butyl ester, 9-ethyl ester.

Also contemplated as intermediates are:

7-(tetrahydropyran-Z-yloxy)-2-dodecyn-4-ol, methanesulfonate. 7-(tetrahydropyran-2-yloxy)-2-dodecyn-4-ol.

These form a family of the formula OTHP wherein THP is tetrahydropyranyland wherein R is methanesulfonyl or hydrogen.

In addtion as valuable intermediates there are con templated:

4- (tetrahydropyran-Z-yloxy)nonanal.4-(tetrahydropyran-Z-yloxy)-2-nonynal. 4-hydroxy-2-nonynal.4-(tetrahydropyran-Z-yloxy)-2-nonynal, diethyl acetal.

These nonanal derivatives comprise a family of the formula wherein R istetrahydropyranyloxy, R is CH and Y is a carbon-to-carbon single bond; Ris tetrahydropyranyloxy, R is CH0 and Y is a carbon-to-carbon triplebond; R is hydroxy, R is CH0 and Y is a carbon-to-carbon triple bond; orR is tetrahydropyranyloxy, R is CH (OCH CH 2 and Y is a carbon-to-carbontriple bond.

Also as valuable intermediates there are contemplated:

4-(3'-methanesulfonyloxy-l'-octenyl) -5-(6'-carboxy-2'-hexenyl)-2-cyclopenten-l-one.

4(3-formyloxy-l'-octenyl)-5-(6'-carboxy-2-hexenyl)- 2-cyclopentenl-one.

4- 3 '-hydroxy-1'-octenyl) -5- (6 '-carb oxy-2'-hexenyl2,3-epoxycyclopentanone.

When used herein and in the appended claims, the term alkyl contemplateshydrocarbon radicals, straight and branched chain, containing from about1 to about 20 carbon atoms, and includes methyl, ethyl, n-propyl,ipropyl, n-butyl, t-butyl, n-pentyl, 3-methylpentyl, n-hexyl, n-heptyl,n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl,n-tetradecyl, n-pentadecyl, n-hexadecyl, nheptadecyl, n-octadecyl,n-nondecyl, n-eicosyl and the like. The term carbo(lower)alkoxy refersto carboxyl groups of the formula -CO R wherein R is (lower) alkyl offrom about 1 to about 6 carbon atoms, as illustrated above including upto n-hexyl. The term (lower)acyloxy contemplates an organic radicalderived from an organic acid containing up to about 7 carbon atoms byremoval of the hydroxyl group and is illustrated by formyloxy, acetoxy,propionyloxy, n-butyroyloxy, secbutyroyloxy, n pentanoyloxy, nhexanoyloxy, cyclopentanoyloxy, benzoyloxy, and the like.

The process of the present invention in its first fourteen abovementioned embodiments may be represented as follows:

wherein R and R are as hereinabove defined.

The first step (1) involves the conversion of the levulinaldehyde (II)with base, e.g., an alkali metal or alkaline earth metal hydroxide,carbonate or obvious chemical equivalent thereof, preferably sodiumhydroxide, under cyclizing conditions into the 2-cyclopenten-l-one(III). In one manner of proceeding a solution or suspension of thealdehyde (II) in about 200 parts by weight of water is treated withabout $5 of its total volume of 5 N sodium hydroxide solution at atemperature of from about 0 C. to about 50 (3., preferably from about 20C. to about 30 C. until cyclization to the corresponding2-cyclopentan-l-one is substantially complete. The time required willvary from about 5 minutes to about 2 to 3 hours, but in most cases, atabout 25 C., 15 minutes is sufiicient. The intermediate of Formula 111can be recovered by any conventional means. One convenient procedure isto extract the reaction mixture with a waterimmiscible organic solvent,such as ether, ethyl acetate,

The 4,5-cis-disubstituted ketone is depicted by Formula IIIb:

H n R n In the case where R =R =methyl, the NMR spectrum of IIIaexhibits a multiplet for the C-5 proton with coupling constants of 7.5and 2.5 cps., which arise from the coupling with the C-5 methyl protonsand the C-4 proton, respectively. The 2.5 cps. coupling constant of the0-4 and C-5 protons is indicative of a dihedral angle of which isconsistant with the trans configuration for these protons. Accordingly,it may be assumed that the prod ucts of the instant proces possessmainly the 4,5-transconfiguration corresponding to the configuration ofthe natural prostaglandin series. In one embodiment of this invention,the trans isomer (IIIa) is separated from the cis isomer (IIIb) toprovide (after using IIIa in steps (2) and (3)) a product containing thetotally synthetic prostaglandin of the natural configuration. Theseparation of isomers is accomplished by any conventional means used inthis series, for example, chromatography, gas liquid chromatography,countercurrent distribution and obviously equivalent means can be used.

The second step (2) involves the treatment of the 4,5- disubstituted 2cyclopenten 1 one of Formula III with alkaline hydrogen peroxide to formthe corresponding 4,5-disubstituted 2,3 epoxycyclopentanone of FormulaIV. The conditions for this conversion involve carrying out the reactionin an alkaline medium (aqueous alkali metal or alkaline earth metalhydroxides, carbonates, or obvious chemical equivalents thereof)preferably an aqueous sodium hydroxide medium with hydrogen peroxide ofmoderate concentrations, e.g., 15 to 50%, preferably about 30%, beingmixed with the 2-cyclopenten-l-one before adding the alkali. Thereaction preferably is conducted at low temperatures, between about thefreezing point of the mixture and about 35 C. In one manner ofproceeding, a solution of 10% sodium hydroxide is added to an ice coldmixture comprising the cyclopentene-l-one of Formula III and about 3parts by weight of 30% hydrogen peroxide, based on the weight of thecyclopentene-l-one. The reaction is substantially complete after about20 minutes at 0 C. The intermediate 4,5 disubstituted 2,3epoxycyclopentanone of Formula IV is recovered by any conventionalmeans. One convenient technique comprises adding about 3 volumes ofwater to the reaction mixture, extracting, the diluted mixture with awater-immiscible organic solvent, such as ether, ethyl acetate,methylene chloride and the like, washing and drying the extract andremoving the solvent by distillation, leaving the compound of Formula IVas a residue.

The third step (3) involves hydrogenolysis of the 4,5-disubstituted-2,3-epoxycyclopentanone by reaction with hydrogen over acatalyst, such as a noble metal catalyst, finely divided or supported,on a carrier, for example, platinum or palladium, or palladium on carbonor palladium on charcoal (which is preferred) until formation of the4,5-disubstituted-B-hydroxycyclopentanone is substantially complete. Inone manner of proceeding, the 4,5-dialkyl- 2,3-epoxycyclopeutanone isabout 4 volumes of a solvent, such as methanol, is mixed with palladizedcharcoal, then reacted with hydrogen at a temperature from about 5 C. toabout 50" 0, preferably at about 25 C. at low to moderate pressures,e.g., from about 1 to about 3 atmospheres, preferably about 1 atmosphereuntil absorption of the equivalent amount or a slight excess, e.g., upto about 1.1 moles of hydrogen is substantially complete. The instantproducts of Formula I are recovered by any conventional technique. Oneconvenient means comprises filtering the reaction mixture and distillingoff the solvent to leave the product as a residue. It may be purified bydistillation in a vacuum or by crystallization from an appropriatesolvent such as a lower alkanol, e.g., methanol or a lower ketone, or alower ester, such as ethyl acetate.

Even where the products of Formula I are prepared without separation ofthe precursor products of Formula III into their trans and cis-isomersIlla and IIIb, respectively, the aforesaid products still consist mainlyof the isomer in which the hydrogens at the 4 and 5-positions are in thetrans-configuration. This is shown for the case in which R =R =methyl bythe transformation of the mixture of4,5-dimethyl-3-hydroxycyclopentanones by base to a mixture containingthe cyclopentenones 111a and IIIb in a ratio of 7:1. This mixture wasseparated by preparative gas liquid chromatography into its twocomponents and proton nmr spectroscopy was used to confirm thestructures assigned to them. For example, the spectrum of compound IIIbin which R =R =methyl displayed a quintet for the O6 proton with a 7.2c.p.s. coupling constant. This pattern arises from overlapping quartetsresulting from coupling with the C-5 methyl protons and the C-4 and C-5protons is indicative of a dihedral angle of 0 which reveals thecis-configurational relationship for these protons.

The process of this invention represented by the fifteenthabove-mentioned embodiment may be represented in the following pathway:

2) unioi OH V VI 1) EtMgBr OTHP 2) ethyl orthoformate OTHP 3) NH Cl011mm 4 (c) VIII VII I Ha0+ OH i OTHP AW 0 ono ono IX (e) X Pd/C (Di HzOTHP OTHP 1 110500113! 0H EtMgBra 2 NHiOl XI 0110 XII \ CHsSOzCl/pyridine l OTHP OBOzCHa XIII COatBu EtOz (11) B1 XIV XIII (1)1 NEHCOW-Bu OTHP (k) l H30+ Cab/A (S) COM-B11 OH EtOzC Etozc WA XVIIa AcO (I)pyiidlne (0 g? flip-TBA (v) 0H Coat-Bu 0A0 XVIII) XIX (u) p' sA XX gk/(n) l p-TSA/A or CaTz/A 0A0 MM XXI OTHP

EtOzC XVIIc (o) NaOH Pg]? (w) XXII CHzN: l (D) on AMA (w) XXIII (q) l D-OTHP AAM XXIV OTHP EtOzO M XVII-d (r) 2) ziiHAc 1) O ziilnAc OTHP EtOzCor B 0010 H0 Ha ment are exemplified in detail hereinafter. Generally,

treatment of hexanal (V) with ethynylmagnesium halide to obtain thealcohol (VI) and the preparation of its THP ether (VII) is accomplishedessentially as reported in J. Med. Chem., 8, 41 (1965). subjecting theGrignard derivative of VII to ethyl orthoformate and decomposing withammonium chloride affords the acetal (VIII). Acid hydrolysis of theacetal provides the hydroxyaldehyde (IX) which will decompose ondistillation. However, the rather impure IX can be converted to its THPether (X), which distills with much less decomposition. Hydrogenation ofX, e.g., with 10% Pd/C in ethyl acetate, yields a stable aldehyde (XI).Treating (XI) with propynyl magnesium halide and decomposing thecomplex, e.g., with ammonium chloride, provides a distillable, viscousalcohol (XII), which can be transformed into the mesylate (XIII) withmesyl chloride in pyridine. The mesylate is very unstable and preferablyis used immediately in step (j). The ethyl 7-bromoheptanoate (XIV)alkylation of t-butylacetoacetate (XV) provides a nonadioic diester(XVI) which is alkylated with the mesylate (XIII), e.g., in the presenceof an alkali metal hydride, e.g., sodium hydride. Acid hydrolysis of theTHP'ether (XVII) followed, e.g., by chromatography, affords the alcohol(XVIII). Acetylation of (XVIII), e.g. with acetic anhydride preferablyin the presence of pyridine provides the acetate (XIX), which ismonohydrogenated, e.g., with a 2% palladium/ CaCO catalyst in ethylacetate, to produce the propene derivative (XX). Decarboxylation of XXto the di-ester (XXI) can be achieved with either p-TSA/llO C./0.5 hr.or with CaI C./ 1.5 hr. Hydrolysis of XXI with 0.5 N sodium hydroxide in50% aqueous ethanol provides XXII which is esterified with diazornethanein ether to produce XXIII. Treatment of XXIII in benzene withdihydropyran and p-TSA afiords XXIV. Alternatively, decarboxylation ofXVII is achieved with CaI 150 C./ 25 min., to produce the alcohol(XVII-a). Monohydrogenation of XVII-a, e.g. with 10% Pd/c in ethylacetate to produce the propene derivative (XVII-d), Ozonolysis of XVII-bwith dihydropyran and p-TSA in benzene affords XXIV. The final twoalternative steps may be reversed by treating XVII-a in benzene withdihydropyran and p-TSA to produce XVII-c followed by monohydrogenationof XVII-c, e.g. with 10% Pd/c in ethyl acetate to produce the propenederivative (XVII-d), Ozonolysis of XVII-d, followed by Zn/Hac work-upgives the desired aldehyde IIa which is converted by the embodimentsdescribed above to dihydroprostaglandin E The process of this inventionrepresented by the six- 17 teenth above-mentioned embodiment may berepresented by the following pathway:

(XXV) H HOZCW W (aa) 1 CHaS O2 Cl/pyridine (XXVI) o s 02 on,

H020 W I (bb) l (onaorrmiio o 011 A/aeetone (XXVII) 0 OH (cc) lalkalineH201 (XXVIII) on (XXIX) on H020 O= OH (dihydroprostaglandin E1) Use ofthe processes of the invention will also lead to compounds havingprostaglandin-like activity when applied to substances derived fromnaturally occurring cyclopentanones such as4-(3'-hydroxy-1-octenyl)-5-(6- carboxy-2-hexenyl)-2-cyclopenten-1-one(XXV) which has recently been isolated (along with its acetate) from theCaribbean gorgonia Plexaura homomalla (A. J. Weinheimer and R. L.Spraggins, Paper 41, Division of Medicinal Chemistry, Abstracts ofPapers, 158th National Meeting of American Chemical Society, Sept. 7-12,1969, Craftsman Press, Inc., Bladensburg, Md.).

Thus XXV, isolated directly from natural sources or throughsaponification of the naturally occurring acetate, is converted withmethanesulfonyl chloride in pyridine to its mesylate XXVI, which isrefluxed in acetone with tetraethylammonium formate, a procedurepreviously used to invert the configuration of hydroxyl groups [8. G.Levine, N. H. Eudy and C. F. Leflier, J. Org. Chem., 31, 3995 (1966); L.F. Fieser and M. Fieser, Reagents for Organic Synthesis, John Wiley andSons, Inc., New York, 1967, p. 1136]. The formate product XXVII treatedwith alkaline hydrogen peroxide gives the epoxide XVIII (epoxidationbeing accompanied by saponification), and the latter, on hydrogenationover a palladium catalyst is converted to an alcohol product XXIXcontaining dihydroprostaglandin E As has been mentioned hereinabove, thecom-pounds prepared by the instant process have valuable pharmacodynamic properties. Notably, a large group of naturally occurring,biologically active prostaglandins and prostaglandin metabolites fallWithin the scope of Formula 1. Thus, dihydro PGE which possesses potentblood pressure lowering and bronchodilator properties is a compound ofFormula I wherein R is 3'-hydroxyoctyl and R is 6'-carboxyhexyl, in atrans relationship. This makes them useful in the control ofhypertension and bronchoconstriction in valuable domestic animals and inlaboratory animals such as mice, rats and rabbits. Furthermore, as alsois mentioned above, the ureide of dihydro PGE and the thiosemicarbazoneof dihydro PGE, are surprisingly effective as bronchodilators, whichmakes them useful to treat experimentally-induced respiratory disordersin warm blooded lower animals, such as guinea pigs.

By way of illustration, for the purposes mentioned above, thebis-p-dimethylaminophenyl ureide of dihydro PGE (also known as1,3-bis(p-dimethylaminophenyl)- 1 [[7 [3 hydroxy 2 (3 hydroxyoctyl) 5oxocyclopentyl] 5 heptanoyl]]urea) can be administered in a variety ofdosage forms, the oral route being used primarily for maintenancetherapy while injectables tend to be useful in acute emergencysituations. Inhalation (aerosols and solution for nebulizers) seems tobe somewhat faster acting than other oral forms but slower thaninjectables and this method combines the advantages of maintenance andmoderately acute stage therapy in one dosage unit.

As is disclosed in 'Ser. No. 672,728 filed Oct. 4, 1967, the daily doserequirements vary with the particular composition being employed and theseverity of the symptoms being presented. The dosage varies with thesize of the patient. With large animals, e.g., about kilograms averagebody weight, by the oral inhalation route, with, for example, a handnebulizer or a pressurized aerosol dispenser, the ordinarily effectivedose from about 5'0 milligrams to about milligrams of the instantcompounds every four hours, as needed. By the oral ingestion route,preferably sublingually, the effective dose is from about 250 to about1000 mg., preferably from about 500 to about 750 mg., up to a total ofabout 3000 mg. per day. By the intravenous route, the ordinarilyeffective dose is from about 50 milligrams to about 250 milligrams,preferably about milligrams per day.

For dosage units, the said prostaglandin ureide compound can becompounded into any of the usual oral dosage forms including tablets,capsules and liquid preparations such as elixirs and suspensionscontaining various coloring, flavoring, stabilizing and flavor maskingsubstances. For compounding oral dosage forms the active ingredient canbe diluted with various tableting materials such as starches of varioustypes, calcium carbonate, lactose, sucrose and dicalcium phosphate tosimplify the tableting and capsulating process. A minor proportion ofmagnesium stearate is useful as a lubricant.

For administration *by the oral inhalation route with conventionalnebulizers or by oxygen aerosolization it is convenient to provide thesaid prostaglandin ureide compound in dilute aqueous solution orsuspension preferably at concentrations of about 1 part of medicament tofrom about 100 to 200 parts by Weight of total preparation. Entirelyconventional additives may be employed to stabilize these preparationsor to provide isotonic media,

' for example, sodium chloride, sodium citrate, citric acid,

sodium bisulfite, and the like may be used.

For administration as a self-propelled dosage unit for administering themedicament in aerosol form suitable for inhalation therapy, thecompounds can be used in compositions comprising the medicamentsuspended in an 19 PROCEDURE A 2,3-Dimethyllevulinaldehyde 5 25 ml. ofpyridine dropwise over /2 hour to 115 g. of

phosphorus tribromide cooled inan ice bath. After stirring for 1 hour atroom temperature, the mixture is distilled to obtain 135 g. of4-bromo-2-pentene, B.P. 22--38/ 12 mm.

Add ethyl a-methylacetoacetate (120 ml.) dropwise to an ice-cooledmixture of 40 g. of 50% sodium hydride-oil dispersion in 500 ml. benzeneand 300 ml. dimethylformamide with stirring under nitrogen. Stir at roomtemperature for 15 min., add 135 g. of the above 4-bromo-2- pentenedropwise and reflux the resulting suspension for 1 hour. Add the cooledmixture to water and extract with ether. Evaporate the Washed and driedextract and distill the residue to obtain 121 g. of the product, B.P.97100/ 3 mm.,

Found (percent): C, 67.58; H, 9.26. Calcd. for C H (percent): C, 67.89;H, 9.50.

(b) 3,4-dimethyl-5-hepten-2-one.-Stir and reflux a mixture of 62.6 g. of2-methyl-2-(1-methyl-2-butenyl) acetoacetic acid, ethyl ester and 200 g.of barium hydroxide in 1.5 liters of water for 2 days. Acidify thecooled mixture with concentrated hydrochloric acid and extract withether. Distill the washed and dried extract to obtain 35.3 g. of theproduct, B.P. 73-77/ 20 mm.,

Found (percent): C, 77.38; H, 11.55. Calcd. for CHI I160 (percent): C,77.09; H, 11.50.

(c) 2,3-dimethyllevulinaldehyde.-Cool a mixture of g. of3,4-dimethyl-5-hepten-2-one, 5.5 ml. of pyridine and 200 ml. methylenechloride in a Dry Ice-acetone bath and ozonize (0 8 p.s.i., 110 volts,flow rate .04) for 70 min. Add the cold solution to 6.0 g. of zinc dust,stir and treat with 13 ml. of acetic acid. Stir the mixture at roomtemperature by cooling with an ice bath when necessary, for 2. hours.Treat the mixture with aqueous Na C0 until basic, adjust to pH 5 withhydrochloric acid, separate and extract with additional methylenechloride. Evaporate the washed and dried extract and distil the liquidto obtain 5.7 g. of 2,3-dimethyllevulinaldehyde, B.P. 60-62/2.5 mm.,

Reported B.P. 7679/12.5 mm. in Helv. Chim. Acta 42, 2746 (1959).

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examplesillustrate the use of the processes of this invention to prepare anumber of valuable compounds. The examples are merely illustrative andare not to be construed to limit the scope of the invention in anymanner whatsoever.

EXAMPLE 1 2-(3'-hydroxyoctyl)-3-(6'-carboxyhexyl)levulinaldehyde andtetrahydropyranyl ether thereof The process of Procedure A is repeatedsubstituting stoichiometricalIy-equivalent amounts of ethyl a-(6-carboethoxyhexylItacetoacetate and6,14-di-tetrahydropyranyloxy-ll-methanesulfonyloxy-9-nonadecene asstarting materials in step (a). The product of step (c) is suspended inaqueous methanol containing about 5% by weight of hydrogen chloride andwarmed to 50 C. for 1 hour. Evaporation of the solvent leaves the titleproduct as a residue.

20 EXAMPLE 2 2-(3'-tetrahydropyranyloxyoctyl)-3 (6'carbomethoxyhexyl)1evulinaldehyde and2-(3'-tetrahydropyranyloxyoctyl)-3-(6'-carboethoxyhexyl)levulinaldehyde(a) Oct-1-yn-3-ol.-Acetylene is passed through 2 solid Co -acetone trapsand bubbled through 1 liter of tetrahydrofuran (THF) for 10 minutes.With acetylene bubbling through the solution, 335 ml. of 3 M is addedwith stirring in small portions over 1 hour. The reaction mixture foamsand refluxes slowly during addition of the Grignard reagent. Theresulting brown suspension is saturated with acetylene for another 10minutes, cooled to 5 C., acetylene is discontinued and the mixture iscooled to -5 C. with a MeOH-ice bath. Freshly distilled hexanal g.) isadded dropwise to the stirred mixture over 1.25 hr. while keeping thetemperature at 0 C. The suspension is stirred at 0 C. for 1 hour,stirred at room temperature for 16 hours, added to 3 liters of saturatedNH Cl and extracted with ether. After washing with water, the ethersolution is dried, evaporated and the residue distilled to give 47 g. ofoct-lyn-3-ol, B.P. 85-90 C./ 1.5 mm. (reported B.P. 75- 85 C./10 mm., J.Med. Chem. 8, 41 [1965]),

762;; 3.1 (5) (hydroxyl and ethynyl C--H) NMR: 4.39 (multiplet, C-3 H),3.41 (5, hydroxyl H), 2.47 (d, J =2 c.p.s., C-l H) p.p.m.

(b) 2-(Oct-1-yn 3 yloxy)tetrahydropyran.-A mixt'ure of 195 g. ofoct-1-yn-3-ol and 153 g. of dihydropyran (purified by standing over KOHpellets for 2 days and distilling from CaH is stirred and cooled to 10C., treated with 6 drops of cone. HCl, stirred at 10 C. for /2 hr. andkept at room temperature for 3 days (only 1 day necessary). The mixtureis treated with 3 pellets of KOH and distilled to obtain 279.4 g. of2-(oct-l-yn-3- yloxy)tetrahydropyran, B.P. 70-88 C./O.3 mm. [reportedB.P. 74 C./0.5 mm., J. Med. Chem. 8, 41

A21; 3.1 (w) (ethynyl C-H) NMR: 2.42 (quartet, ethynyl H) p.p.m.

(c) 4-(tetrahydropyran-Z-yloxy) 2 nonynal, diethyl acetal.A solution of192.2 g. of 2-(oct-1-yn-3-yloxy) tetrahydropyran in 250 ml. of ether isadded dropwise under nitrogen during hour to 410 ml. of 3 M EtMgBretherwith stirring. After refluxing for /2 hour, 177 g. of ethyl orthoformateis added and the mixture refluxed for 18 hours. The resulting suspensionis added to 2 liters of saturated NH,Cl and extracted with ether. Afterwashing With Water, the ether extract is dried, evaporated and theresidue distilled to obtain 219.8 g. of product, B.P. C./0.2 mm. Ananalytical sample exhibits B.P. 143 C./0.15 mm.,

A2,; 3.50, 7.55, 8.95, 9.50, 9.80 NMR: 5.32 (s, C-1 H), 1.25 (t, J=7c.p.s., ethyl CH Analysis.Found (percent): C, 69.19; H, 10.11. C H Orequires (percent): C, 69.19; H, 10.32.

(d) 4-hydroxy-2-nonynal.-A solution of 216.8 g. of4-(tetrahydropyran-Z-yloxy)-2-nonyna1, diethyl acetal in 1.1 liters of'I'HF is treated with 210 ml. of 30% H 80 and the mixture stirred at 25C. for 5.5 hr. The mixture is diluted with 4 liters of Water andextracted with ether. After washing with 5% KHCO, and water, the etherextract is dried and evaporated to yield 169.1 g. of4-hydroxy-Z-nonynal,

)3; 3.0 M dro l 4.5 w C=C 5.93 s (aldehydeaibcs gl) L 0 (e)4-(tetrahydropyran-2-yloxy)2-nonynal.A stirred mixture of 169 g. of4-hydroxy-2-nonynal and 127 g. of dihydropyran is treated with 12 dropsof concentrated I-ICl and the reaction temperature maintained for /2hour at 2025 C. with an ice bath. After stirring at 21 room temperaturefor 4 hours, the mixture is diluted with 1 liter of ether, washed with5% KHCO water and dried. Evaporation and distillation of the residueaffords 114.5 g. of 4-(tetrahydropyran-2-yloxy)-2-nonynal, B.P. 100-120C./0.2 mm.,

A2,; 4.53 (M) (C C), 5.95 (s) (aldehyde carbonyl) p.

(f) 4-(ttetrahydropyran-Z-yloxy)nonanal.A solution of 22.9 g. of4-(tetrahydropyran-Z-yloxy)-2-nonynal in 75 ml. of ethyl acetate isadded to 4.5 g. of 10% Pd/C prehydrogenated in 100 1111. of ethylacetate and the mixture is hydrogenated at 25 C. and atmosphericpressure. When 2.1 equivalents of hydrogen are absorbed, the reactionmixture is filtered, evaporated and distilled to give 14.7 g. of4-(tetrahydropyran-2-yloxy)-nonynal. The analytical sample exhibits B.P.100-102 C./0.05 mm.,

Al; 3.75 (w) (aldehyde hydrogen), 5.80 (s) (aldehyde carbonyl) 1.

NMR: 9.83 (multiplet, aldehyde H), 4.63 (broad singlet) and 3.68 (3proton multiplet, OCH protons), 2.57 (diffuse quartet, J=7 c.p.s., C,u.protons) p.p.m.

Analysis.-Found (percent): C, 69.31; H, 10.80. C H O requires (percent):C, 69.38; H, 10.81.

(g) 7 (tetrahydropyran-Z-yloxy)-2-d0decyn4-ol.-A solution of 60 g. ofpropyne in 800 ml. of THF is added dropwise over 1 hr. to 168 ml. of 3 MEtMgBr/ether with stirring under nitrogen. After bubbling propynethrough the reaction mixture for 15 min., the mixture is cooled to -5 C.with methanol-ice and 82.2 g. of 4- (tetrahydropyran-Z-yloxy)nonanal in150 ml. of THF is added dropwise over /2 hour while maintaining thetemperature at C. After stirring at 0 C. for /2 hour and at 25 C. for 2hours, the mixture is added to 3 liters of saturated NH Cl solution andextracted with ether. The extract is washed with water, dried,evaporated and distilled to obtain 76.3 g. of product (a viscous oil),B.P. 130145 C./0.05 mm.,

A33; 3.00 (M) (hydroxy) n NMR: 1.72 (broad singlet, propynyl methyl)p.p.m.

Analysis.--Found (percent): C, 72.02; H, 10.91. C H O requires C, 72.30;H, 10.71.

(h) 2-acetylnonadioic acid, l-t-butyl ester, 9-ethy1 ester.t-butylacetoacetate (14.6 g.) is added dropwise over /2 hour to a stirredmixture of 4.0 g. of 50% NaH-mineral oil in 20 ml. of dimethyl formamideand 40 ml. of benzene under nitrogen. After stirring at 25 C. for 1hour, 10.0 g. of ethyl 7-bromoheptanoate is added and the mixture isrefluxed for /2 hour, then diluted with water and extracted with ether.After washing with 5% NaOH and water, the extract is dried, evaporatedand the residue chromatographed on silica. Elution with 1:19ether-benzene affords 14.2 g. of product,

XL; 5.80 (s) (carbonyls) u NMR: 4.14 (quartet, I 7 c.p.s., ethyl CH 3.32(triplet, J 7 c.p.s., C-2 H). 2.28 (multiplet, C-8 protons), 2.20(singlet, acetyl methyl), 1.47 (singlet, t-butyl protons), 1.25(triplet, J 7 c.p.s., ethyl CH p.p.m.

A alysis.--Found (percent): C, 64.98; H, 9.33. C H O requires (percent):C, 64.94; H, 9.62.

(i) 7-(tetrahydropyran-2-yloxy) 2 dodecyn-4-ol, methanesulfonate.Anice-cooled mixture of 19.9 g. of7-(tetrahydropyran-Z-yloxy)-2-dodecyn-4-ol and 8.0 ml. of pyridine istreated with 6.0 ml. of methanesulfonyl chloride and stirred for 15minutes. The resulting viscous suspension is kept at 0 C. for 12 hours,diluted with ether and filtered. The ether solution is washed thricewith water, once with brine, filtered through Na SO and dried over MgSOfor 2 hours. After filtration and evaporating of the ether at 30 C./20mm., the residue is stirred under 0.005 mm. pressure at 25 C. for 2hours to give 23.2 g. of crude 7-(tetrahydropyran-Z-yloxy)-2-dodecyn-4-ol, methanesulfonate,

A2,; 4.50 (w) (C O), 7.35 and 8.50 (s) (mesylate) NMR: 5.22 (broadmultiplet, C-4 H), 3.11 (s, mesylate CH 1.92 (doublet, propynyl CHp.p.m. Since the mesylate decomposes to a black tar after 16 hours at 25C. the crude product is immediately used in the next step.

(j) 2-acetyl-2-[l-(l-propynyl) 4 tetrahydropyran-2-yloxy)nonyl]nonanedioic acid, l-t-butyl, 9-ethyl ester.- To a stirredmixture of 3.02 g. of 50% NaH-oil in 6 ml. of benzene and 30 ml. DMFunder nitrogen, 19.8 g. of 2-acetyl-1,9-nonadioic acid, l-t-butyl ester,9-ethyl ester is added dropwise over 15 minutes. After stirring at 25 C.for /2 hour, 22.95 g. of the mesylate of step (i) is added and themixture is refluxed for /2 hour. The cooled reaction mixture is dilutedwith water, extracted with ether and the extract washed with water,dried, and evaporated. Chromatography of the residue on alumina(activity 3, neutral) and elution with benzene affords 22.3 g. ofproduct, a viscous oil,

REE; 5.80 (s) (carbonyl) ,3

NMR: 4.68 (broad multiplet, O-CHO), 4.13 (quartet, I =7 c.p.s., ethyl CH2.25 (multiplet, C2 protons and acetyl CH 1.77 and 1.80 (propynyl CH1.48 (s, t-butyl protons), 1.25 (t, J =7 c.p.s., ethyl CH p.p.m.

Analysi .Found (percent): C, 70.12; H, 10.04. C34H5807 requires(percent): C, 70.55; H, 10.10.

(k) 2 acetyl-2-[4-hydroxy-1-(1-propynyl)-nonyl]nonanedioic acid,l-t-butyl, 9-ethyl ester.-A solution of 20.2 g. of2-acetyl-2-[1-(1-propynyl)-4- (tetrahydropyran-2-yloxy)nonyl]nonanedi0ic acid, l-tert-butyl 9-ethyl ester in 200 ml. ofTHF is treated with 70 ml. of 6 N HCl and the 2 phase mixture is stirredfor 1 hour while maintaining the temperature at 25 C. with an ice-bathas necessary. The mixture is diluted with water, extracted with etherand the extract washed with 5% KHCO water and dried. Evaporation andchromatography of the residue on alumina (neutral, Activity 3) followedby elution with 1:19 ether-benzene afiords 10.9 g. of product, a viscousoil,

A213; 2.90 (M) (hydroxyl), 5.80 (s) (carbonyl) NMR: 4.13 (q, J=7 c.p.s.,ethyl CH 3.66 (broad multiplet, C-12 H), 2.95 (broad multiplet, C-9 H),2.30 (multiplet, C-2 protons), 2.20 and 2.23 (acetyl CH 1.78

and 1.81 (propynyl CH 1.48 (s, t-butyl protons), 1.25 (t, J=7 c.p.s.,ethyl CH p.p.m.

Analysis.Found (percent): C, 70.30; H, 10.00. C H O requires (percent):C, 70.41; H, 10.19.

(1) 2-acetyl 2 [4-hydroxy-1-(1propynyl)nonyl]nonanedioic acid,l-t-butyl, 9-ethyl ester, acetate.A solu tion of 5.3 g. of2-acetyl-2-[4-hydroxy-1-(1-propynyl)nonyl]nonanedioic acid, l-tert-butyl9-ethyl ester in 50 ml. of pyridine and 6.4 m1. of acetic anhydride iskept at 25 C. for 16 hours. The mixture is diluted with water, extractedwith ether and the extract is washed with 2 N HCl, water and dried.Evaporation of the extract and chromatography of the residue on alumina(neutral, Activity 3) followed by elution with benzene aifords 3.6 g. ofproduct, a viscous oil,

A1; 5.78 (s) (carbonyl) ,1

NMR: 4.86 (broad multiplet, C-12 H), 4.09 (q, I=7 c.p.s., ethyl CH 2.85(broad multiplet, C-9 H), 2.26 (multiplet, C-2 protons), 2.16 and 2.18(acetyl CH 2.00 (s, acetate CH 1.75 and 1.78 (propynyl CH 1.45 and 1.47(t-butyl protons), 1.23 (t, i=7 c.p.s., ethyl CH Analysis.-Found(percent): C, 69.26; H, 9.62. C H O requires (percent): C, 69.37; H,9.77.

(m) 2 acetyl-2- [4-hydroxy- 1-(1 propenyl)nonyl]nonanedioic acid,l-t-butyl, 9-ethyl ester, acetate.-A solution of 4.1 g. of 2acety1-2-[4-hydroxyl-1-(l-propynyl) nonyl]nonanedioic acid, l-tert-butyl9-ethyl acetate in 40 ml. of ethyl acetate is added to 0.8 g. of 2%ld/CaCO A 5.80 (s) (carbonyl) max.

NMR: 4.6-5.8 (dilfuse multiplet, C-l2 H and olefinic protons), 4.10 (q,1:7 c.p.s., ethyl CH 2.97 (broad multiplet, C-9 H), 2.26 (multiplet, C-2protons), 2.14 (s, acetyl CH 2.00 (s, acetate CH 1.61 and 1.63 (d, J=6.5c.p.s., propenyl CH 1.48 (s, t-butyl protons),

1.23 (t, J =7 c.p.s., ethyl CH p.p.m.

Analysis.-Found (percent): C, 69.20; H, 9.80. C H O requires (percent):C, 69.11; H, 10.10.

(11) 8 acetyl-12-hydroxy-9-(1-propenyl)heptadecanoic acid, ethyl ester,acetate.p-toluenesulfonic acid (82 mg.) is added to 2.3 g. of2-acetyl-2-[4-hydroxy-1-(1-propenyl) nonyl] nonanedioic acid,l-tert-butyl, 9-ethyl ester, acetate, stirring under nitrogen at 110 C.and the mixture is stirred for 1% hours. The cooled mixture is dilutedwith ether, washed with 5% IKHCOQ, water and dried. Evaporation andchromatography of the residue on neutral alumina (Activity 3) followedby elution with 1:1 hexanebenzene affords 0.9 g. of the title product, a2:1 mixture of 2 close stereoisomers on TLC and GPC,

73. 2;. 5.75 (s) (carbonyl) a NMR: 4.6-5.8 (diffuse multiplet, C-12 andolefinic protons), 4.09 (q, I 7 c.p.s., ethyl CH 1.9-2.8 (10 protonmultiplet; acetyl CH acetate CH C-2, C-8 and C-9 protons), 1.59 (d, J 7c.p.s., propenyl CH 1.23 (t, J 7 c.p.s., ethyl CH ppm.

Analysis.Found (percent): C, 71.22; H, 10.60. C H O requires (percent):C. 71.19; H, 10.57.

8 acetyl-12-hydroxy-9-(1-propenyl)heptadecanoic acid-The product of step(11) (6.9 g.) is stirred at 25 C. for 4.5 hrs. in 100 ml. of ethanol and1000 ml. of 1 N aqueous sodium hydroxide. Dilute the mixture with waterand extract with ether to obtain 6.1 g. of the title compound,

A ie 3.0, 5.911. NMR: 5.3 (broad multiplet, olefinic proton), 2.07 and2.15 (singlets, acetyl CH 1.67 (doublet J 6 c.p.s., propenyl CH p.p.m.

(p) 8 acetyl-12-hydroxy-9-(l-propenyDheptadecanoic acid, methylester.The product of step (0) (6.0 g.) is treated with excessdiazomethane in ethyl ether for 1 hr. at 25 C. Decompose the excessdiazornethane with acetic acid, wash the mixture with water andevaporate to obtain 5.8 g. of the title compound,

REE; 3.0, 5.75, 5.85;

NMR: 5.3 (broad multiplet, olefim'c protons), 3.65 (singlet, methylester), 2.05 and 2.14 (singlets, acetylCH 1.62 (doublet, J c.p.s.,propenyl CH p.p.m.

(r) 2-(3'-tetrahydropyranyloxyoctyl)-3(6'-carbomethoxyhexyl)levulinaldehyde.The product of step (q) (1.8 g.)is ozonized in 70 ml. of methylene chloride and 0.32 ml. of pyridine at-70 C. until a blue color develops. Treat the cold solution with 2.32 g.of powdered zinc and 4.7 ml. of acetic acid. After stirring at 25 C. for1 hr., filter the mixture, dilute the filtrate with ether, wash withwater and evaporate. The resulting residue is dissolved in benzene,filtered through alumina and evaporated to obtain 1.5 g. of the titlecompound,

NMR: 9.55 (multiplet, aldehyde proton), 3.65 (singlet, methyl ester),2.24 and 2:16 (singlets, acetyl CH p.p.m. (s) 8-acetyl-l2-hydroxy9-(l-propynyl)heptadecanoic acid, ethyl ester.Stir 9.7 g. of2-acetyl-2-[1-(l-propynyl)-4-(tetrahydtopyran-2 yloxy)nonyl] nonanedioicacid, l-tert-butyl-9-ethyl ester [Example 2(j)] under nitrogen at atemperature of 150 C. and add 2.44 g. of calcium iodide. Continuestirring at 150 for 25 minutes, cool and dissolve the reaction productin ether and water. Separate and wash the ether layer with aqueoussodium chloride solution, dry over MgSO and evaporate. Chromatography ofthe residue on neutral alumina and elution with 1:9 ether-benzeneaffords 2.2 g. of the title product,

A23, 2.9 (hydroxyl), 5.8 (carbonyl) n .-(t) 8-acetyl-12-hydroxy--9-(1-propenyl)heptadecanoic acid, ethyl ester.Add a solution of 7.1 g.of 8-acetyl-. 12-hydroxy-9 (1-propynyl)heptadecanoic acid, ethyl ester[step (s)] in ml. of ethyl acetate to 1.4 g. of 10% Pd/charcoalprehydrogenated in 100 ml. of ethyl acetate and hydrogenate at 25 andatmospheric pressure until 1 equivalent of hydrogen is absorbed. Filterthe catalyst and evaporate to obtain 7.0 g. of the title product;

A23, 2.9 (hydroxyl), 5.8 (carbonyl), 13.8 (double bond) 1.

mass spec; m/ e 396 (molecular ion).

(u) 8-acetyl 9-(1-propenyl) 12-(tetrahydropyran-2- yloxy)heptadecan0icacid, ethyl ester.Treat a solution of 7.2' g. of8-acetyl-l2-hydroxy-9-(1-propenyl)heptadecanoic acid, ethyl ester [step(t)] and 4.8 g. of dihydropyran in ml. of benzene with 280 mg. ofptoluenesulfonic acid and stir at 25 for 20 minutes. Dilute the reactionmixture with ether, wash with water, dry and evaporate. Chromatographthe residue on neutral alumina and elute with 1:1 benzene-hexane toobtain 2.8 g. of the title product,

7sf,}$,'5.7and'5.8 (carbonyls), 13.7 (double bond) u (v)8acetyl-9-(1-propynyl) 12-(tetrahydropyran-2- yl oxy)heptadecanoic acid,ethyl ester.-Treat a solution of 1.3 g. .of 8- acetyll2-hydroxy-9-(l-propynyl)heptadecanoic acid, ethyl ester [step (s)] and 0.87 g.ofdihydropyran in 25 ml. oi benzene with 50 mg. of p-toluenesulfonicacid ands'tir at 25 ,for 20 minutes. Dilute the reaction mixture withether, wash with water, dry and evaporate to obtain 1.6 g. of the titleproduct,

hill; 5 and 5.80 (carbonyls) (W) 8-acetyl-9-(l-propenyl)l2-(tetrahydropyran-2- yloxy)heptadecanoic acid, ethyl ester.Add asolution of 0.5 g. of 8-acetyl-9-(1-propynyl)-12-(tetrahydropyran-2-yloxy)heptadecanoic acid, ethyl ester [step (v)] in 10 ml. of ethylacetate to 0.1 g. of 10% Pd/charcoal prehydrogenatedin 15 ml. of ethylacetate and hydrogenate at 25 and atmospheric pressure until 1equivalent of hydrogen is absorbed. Filter the catalyst and evaporate toobtain 0.47 g. of the title product.

'(x) 2-(3'-tetrahydropyranyloxyoctyl) 3(6'-carboethoxyhexyl)levulinaldehyde.The product of step (W) (2.3g'.)"is ozonizecl in 70 ml. of methylene chloride and 0.4ml. of pyridineat -70 C. until a blue color develops followed by treating the coldsoltuion with 3.0 gm. of powdered zinc and 6.0 ml. of acetic acid. Afterstirring at 25 C. for one-half hour, filter the mixture, dilute thefiltrate with ether, wash with water and evaporate. The resultingresidue is dissolved in benzene, filtered through alumina and evaporatedto obtain 1.6 g. of the title compound, r

25 26 Nil; 5.75, 9.70.11 EXAMPLE 6 NMRi 9.6 (multiplet, aldehydeproton), 4.13 (quartet), Y Y Y Y 2.18 (singlet). 2-cyclopenten-1-one IEXAMPLE 3 i 2-(3-ace-toxyoctyl)-3-(6' carboethoxyhexyl)luvelinal- Theprocess of ProcedureA is repeated substituting, 5 dehyde iST'nade P intof y Weight a in St p (a), appropriately-substituted starting materials0.1 N solution of NaQH in 2:1 dloxane-water for minand the following2,3-disubstituted levulinaldehydes are Utes at C- The re 1S ev p r d todryness 111 a obtained: vacuum and the residue is extracted withmethylene chlo- R R =2 orro CHz(CH2)1sCH3 CH2(CH2)isC 3CHKCHzhCHgCOzCHflCHzhCH: CH2(CH2)18CH3 CH2(CH2)4CH:C OzCHa O ride.Evaporation leaves a 75% yield of neutral product EXAMPLE 4 2 which ischromatographed on alumina to obtain pure l Y P title compound, alsonamed ethyl ester, acetate of dihydro Treat a solmion of 1L8 of 23d-Lmethy11evu1ina1de PG A with infrared and ultraviolet spectra, nuclearmaghyde in 2 liters of water with 220 m1. of 5 N sodium netlc msonancespectrum gas Phase chromatography hydroxide and stir for 15 mm at roomtemperature mass spectrum and micro analysis consistent with the Extractthe mixture with methylene chloride and distill Structure the washed anddried extract to obtain 6.3 g. of the title EXAMPLE 7 product, B.P.'5963/ 10 IDIIL, 4-(3'-hydroxyoctyl)-5-(6-carboxyhexyl)- Found(percent): 0, 76.52; H, 9.46. Calcd. for C7H1O-O A solution of of py yy- (percent): 0, 76.32; H, 9.15. NMR: 7.59 (1 proton y y y y p equartet, J 6 and 2.5 c.p.s., C-3H), 6.113 (1 proton quartet, P 5 1n 9tfiftl'ahydloflllall d 50 1- f 1 N J 6 and 2 c 2 2,55 1 proton difif m.hydrochloric acid is stirred at 25 C. for 0.5 hour. Dilute plot, 04 H),1.88 1 proton octet, J 7.5 and 2.5 c.p.s., 40 the mixture With Waterzextract wi ether evaporate and c-s H), 1.22 and 1.17 3 proton doublets,J 7 c.p.s., chromatograph the resldue on slhca to obtain of methylgroups) p.p.m. the title compound,

EXAMPLE 5 A331. 3 5- 4 (3' tetrahydropyranyloxyoctyl) s (6rcarboxyhexyl) NMR; 7.60 and 6.13 (multiplets, olefinic protons), 3.66

gscyclopentempone and methyl ester thereof (multiplet, OCH proton), 2.33(triplet, J 7 c.p.s., methlene ad'acent to carbon 1 .m. Treat a solutionof 1.5 g. of 2-(3'-tetrahydropyrany1- y pp oxyoctyl)-3 (6carbomethoxyhexyl) levulinaldehyde 7 EXAMPLE 8 (Example 2) in 200 m1. ofdi Xane and 92 1111- f Wat The procedure of Example 4 is repeatedsubstituting the with 6.1 ml. of '5 N aqueous sodium hydroxide and stir2,3-disubstituted levulinaldehydes of Examples 3 as startthe mixture at25 c. for 0.5 hour. Dilute the mixture ing materials. The following4,5-disubstituted-Z-cyclopenwith water, acidity and extract with ether.Evaporate ten-l-ones are obtained.

H R1 R H a; ir"

CHz(CH2)mCHa CH2(CH2)1&CH3 CHZ(CH )4CH2C02CH2(CH2)4CHs OH2(CH2)1BCH3 theextract and chromatograph the residue on silica to EXAMPLE 9 obtain 1.2g. of the title compound,

AR 530 5.88, 630 4,5-d1methyl-2,3-epoxycyclopentanone NMR: 7.58 and 6.12(multiplets, olefinic protons), 4.65 Add 10 m1. of 10% sodium hydroxidedropwise to a and 3.60 (multiplets, O0H protons), 2.33 (triplet, Jice-cooled mixture of 9.1 g. of 4,5-dimethyl-2-cyclopen- 7 c.p.s.methylene adjacent to carbonyl) p.p.m. ten-l-one and 27 ml. of 30%hydrogen peroxide in 35 If the reaction is terminated after 35 minutes,the ml. of methanol. After stirring the mixture at 0 C. for

methyl'ester of the title compound is isolated. 20 min., dilute with m1.of water and extract with 27 ether. Distill the washed and dried extractto obtain 5.3 g. of the product, B.P. 75-77 10 mm.,

N3; 5.75;. NMR: 3.72 and 3.35 (1 proton multiplets, C-2 and O-3 Hs),2.04 (2 proton multiplet, W V2-43 c.p.s., C -4 and C-5 Hs), 1.12 (6proton multiplet, methyl groups) p.p.m.

EXAMPLE 1'0 4- (3 '-hydroxyo ctyl) -5- 6'-carb oxyhexyl)2,3-epoxyeyclpentanone An ice-cooled solution of 0.23 g. of4-(3-hydroxyoctyl)--(6'-carboxyhexy1)-2-cyclopenten-1-one (Example 7) in4 ml. of methanol and 1 mil. of water is treated with 0.2 m1. of 30%hydrogen peroxide and 0.87 ml. of 1 N sodium hydroxide and the mixturestirred at 0 C. for 10 minutes. Acidity the mixture with acetic acid,dilute with water and extract with ether to obtain 0.22 g. of the titlecompound ire, 3.0, 5.85

NMR: 3.72 and 3.37 (multiplets, C-2 and C-3 protons), 3.65 (multiplet,C-3 octyl proton), 2.33 (triplets, J 7 c.p.s., methylene adjacent tocarboxyl).

EXAMPLE 11 4- (3f-tetrahydropyranyloxyo ctyl) -5- 6-carboxyhexyl) I2,3-epoxycyclopentanone and methyl ester The procedure of Example 10 isrepeated substituting 4 (3'tetrahydropyranyloxyoctyl)-5-(6'-carboxyhexyl)- Z-cyclopenten-l-one asstarting material and the product is obtained. The methyl ester ofExample 5 is converted by the procedure of Example 10 to thecorresponding methyl ester.

EXAMPLE 12 The procedure of Example 9 is repeated substituting the4,5-disubstituted -2-cyclopenten-1-ones of Example 8 as startingmaterials and the following 4,5-disubstituted 2,3-epoxycyelopentanonesare obtained:

HR R H 28 40 ml. of methanol and hydrogenate at 25 C. and atmosphericpressure. After an uptake of 1.1M of hydrogen, filter and distill toobtain 1.4 g. of the product, B.P. 73- 75/0.1 -mm.,

7&3, 3.0, 5.78 NMR: 4.10 (1 proton multiplet, C-3 H), 3.76 (1 protonsinglet, hydroxyl proton), LSD-3.0 (4 proton complex, C2, C-4 and C-5Hs), 1.11 (6 proton multiplet, methyl groups) ppm.

EXAMPLE 14 4- (3 '-hydroxyoctyl -5- (6'-carboxyhexyl -3-hydroxycyclopentanone and 3'-tetrahydropyranyl ether thereof (a) Asolution of 200 mg. of 4-(3'-hydr0xyoctyl)-5-(6-carboxyhexyl)-2,3-epoxyoyclopentanone (Example 10) in 5 ml. of methanolis added to mg. 015.10% Pd/c in 10 ml. of methanol and 0.1 ml. ofsaturated aqueous sodium acetate and the mixture hydrogenated at 25 C.and atmospheric pressure. Filter, evaporate and chromatograph theresidue on silica to obtain the title compound.

(b) The above reaction is repeated substituting 4-(3'-tetrahydropyranyloxyoctyl) 5 (6'-carboxyhexyl 2,3- epoxycyclopentanone(Example 11) as starting material and the resulting product,4-(3-tetrahydropyranyloxyoctyl) -5- (6-carboxyhexyl) -3-hydroxycyclopentanone, is hydrolyzed with 0.5 N hydrochloric acid in50% aqueous tetrahydrofuran at 25 C. for 0.5 hr. to obtain the titlecompound. I

EXAMPLE 15 4-( 3acetoxyoctyl)-5-(6'-carboethoxyhexyl)-3-hydroxycyclopentanone Theprocedure of Example 14 is repeated substituting 4-(3' acetoxyoctyl) 5(6'-carboethoxyhexyl) 2,3- epoxycyclopentanone as starting material andthe product is obtained.

EXAMPLE 16 The procedure of Example 13 is repeated substituting the4,5-disubstituted-2,3-epoxycyclopentanones of Exomwmrronzoozon '0 ItCHzCHzCHIOCCHKCHzhCHKK HQsCH;

EXAMPLE 13 4,5-dimethyl-3-hydroxycyelopentanone Add 4.6 g. of4,5-dimethyl-2,3-epoxypentanone in 15 ml. of methanol to 2.0 g. of 10%palladized charcoal in ample 12 and corresponding 2,3-epoxides obtainedby entirely analogous processes as starting materials and the following4,5-disubstituted 3-hydroxycyclopentanones are obtained:

R B B:

0 MNOH CHzCHaCEHO 1 CHKCHEMCHaKCHzhCH;

29 EXZAMPLE 17 The procedure of Example 13 is repeated, substituting forthe palladized charcoal catalyst, equivalent amounts of the followingcatalysts: palladium on carbon, platinum, and unsupported palladium.Substantially the same results are obtained.

EXAMPLE 18 The product of Example 4 is separated into its 4,5- cis and4,5-trans isomers by preparative scale gas liquid chromatography using a5 foot column of 20% SE-30 (a silicone rubber gum) on Chromosorb W (aninert chromatographic support) at a column temperature of 104 C. withnitrogen as a carrier gas at 2 pounds per square inch gauge pressure.The trans-isomer is converted to the corresponding4,5-trans-4,5-dimethyl-3-hydroxycyclopentanone by the procedures ofExamples 9 and 13.

EXAMPLE 19 (aa) 4-(3'-methanesulfonyloxy 1 octenyl) 5 (6-carboxy-2'-hexenyl)-2-cyclopenten-1-one.-Treat an icecooled solution of4-(3-hydroxy-1-octenyl)-5-(6'-carboxy-2'-hexenyl)-2-cyclopenten-one inpyridine with one equivalent of methanesulfonyl chloride and keep themixture at for sixteen hours. Add the reaction mixture to water, acidifywith hydrochloric acid and extract with ether. After washing the extractwith water, dry and evaporate under reduced pressure to obtain the titleproduct.

(=bb) 4-(3' formyloxy 1' octenyl)(6'-carboxy-2'-hexenyl)-2-cyclopenten-l-one.Reflux a solution of4-(3'-methanesulfonyloxy-l'-octenyl)-5-(6'-carboxy-2'-hexenyl)-2-cyclopenten-1-one and four equivalents of tetraethylammoniumformate in acetone for seventeen hours. Remove the acetone under reducedpressure, add water and extract with ether. Wash the extract With water,dry, evaporate and chromatograph the residue on silica gel to obtain thetitle product.

(cc) 4-(3' hydroxy-1-octenyl) 5 (6-carboxy-2-hexenyl)-2,3-epoxycyclopentanone.Treat an ice cooled solution of4-(3'-formyloxy-1'-octenyl)-5-(6'-carboxy-2'-hexenyl)-2-cyclopenten-1-one and four equivalents of hydrogen peroxidein 20% aqueous methanol with 2.5 equivalents of 10% sodium hydroxidesolution and stir the mixture at 0 for one-half hour. Acidify themixture with acetic acid, dilute with water and extract with ether toobtain the title product.

(dd) 4-(3 hydroxoctyl) 5 (6"-carboxyhexyl)-3-hydroxycyclopentanone.-Adda methanolic solution of 4- (3'-hydroxy-1'-octenyl) 5(6-carboxy-2'-hexenyl)-2,3- epoxycyclopentanone to a suspension of 10%Pd/C in methanol containing 1% of saturated aqueous sodium acetatesolution and hydrogenate at 25 and atmospheric pressure until threemolar equivalents of hydrogen are 30 absorbed. Filter, evaporate andchromatograph the residue on silica to obtain the title product. Theidentity of the compound is confirmed by comparing with previouslyproduced compounds of the same formula.

As will be obvious to those skilled in the art, because of centers ofasymmetry, many of the compounds of Formula I prepared by this inventionare capable of being optical isomers. It is a matter of common knowledgeand experience that naturally-occurring prostaglandins and metabolitesthereof are optically-active. The instant total synthesis provides meansto obtain products of Formula I either in racemic or in optically-activeform. In the product of the synthesis which has not included a suitableresolution stage (e.g., by resolving the diastereomeric mixed salt of anoptically-active base with an appropriate acidic intermediate shownherein, or by resolving a diastereomeric mixed ester of a carbinolintermediate shown herein with an optically-active acylating agent), thecompounds of Formula I prepared by the invention will be present asracemates. The optically-active enantiomorphs can be prepared usingoptically active intermediates or they can be obtained by resolvingracemic products of Formula I by well-known procedures.

What is claimed is:

1. A compound of the formula HR R H References Cited Chemical Abstracts,vol. 51 (1957), p. 8021. Jour. Am. Chem. Soc. 89 (13) (1967), pp.3363-4.

NORMA S. MILESTONE, Primary Examiner US. Cl. X.R.

260345.8, 348 C, 405, 456, 468, 483, 488 R, 514 R, 586 R, 595, 601 R,602 R, 632 Y; 424-305, 318

